4-(Phenyl-(piperidin-4-yl)-amino)-benzamide derivaties and their use for the treatment of pain, anxiety or gastrointestinal disorders

ABSTRACT

Compounds of general formula (1): R 1  is selected from any one of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, pyrrolyl, triazolyl, thiazolyl and pyridine N-oxide; where each R 1  phenyl ring and R 1  heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C 1 -C 6  alkyl, NO 2 , CF 3 , C 1 -C 6  alkoxy, chloro, fluoro, bromo, and iodo. The substitutions on the phenyl ring and on the heteroaromatic ring may take place in any position on said ring systems; are disclosed and claimed in the present application, as well as salts and pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain, anxiety and functional gastrointestinal disorders.

FIELD OF THE INVENTION

[0001] The present invention is directed to novel compounds, to aprocess for their preparation, their use and pharmaceutical compositionscomprising the novel compounds. The novel compounds are useful intherapy, and in particular for the treatment of pain, anxiety andfunctional gastrointestinal disorders.

BACKGROUND OF THE INVENTION

[0002] The δ receptor has been identified as having a role in manybodily functions such as circulatory and pain systems. Ligands for the δreceptor may therefore find potential use as analgesics, and/or asantihypertensive agents. Ligands for the δ receptor have also been shownto possess immunomodulatory activities.

[0003] The identification of at least three different populations ofopioid receptors (μ, δ and κ) is now well established and all three areapparent in both central and peripheral nervous systems of many speciesincluding man. Analgesia has been observed in various animal models whenone or more of these receptors has been activated.

[0004] With few exceptions, currently available selective opioid δligands are peptidic in nature and are unsuitable for administration bysystemic routes. One example of a non-peptidic δ-agonist is SNC80(Bilsky E. J. et al., Journal of Pharmacology and ExperimentalTherapeutics, 273(1), pp. 359-366 (1995)). There is however still a needfor selective δ-agonists having not only improved selectivity, but alsoan improved side-effect profile.

[0005] Thus, the problem underlying the present invention was to findnew analgesics having improved analgesic effects, but also with animproved side-effect profile over current μ agonists, as well as havingimproved systemic efficacy.

[0006] Analgesics that have been identified and are existing in theprior art have many disadvantages in that they suffer from poorpharmacokinetics and are not analgesic when administered by systemicroutes. Also, it has been documented that preferred δ agonist compounds,described within the prior art, show significant convulsive effects whenadministered systemically.

[0007] We have now found certain compounds that exhibit surprisinglyimproved properties, i.a. improved δ-agonist potency, in vivo potency,pharmacokinetic, bioavailability, in vitro stability and/or lowertoxicity.

Outline of the Invention

[0008] The novel compounds according to the present invention aredefined by the formula I

[0009] wherein

[0010] R¹ is selected from any one of

[0011] (i) phenyl;

[0012] (ii) pyridinyl

[0013] (iii) tienyl

[0014] (iv) fuiranyl

[0015] (v) imidazolyl

[0016] (vi) triazolyl

[0017] (vii) pyrrolyl

[0018] (viii) thiazolyl

[0019] (ix) pyridyl-N-oxide

[0020]  where each R¹ phenyl ring and R¹ heteroaromatic ring mayoptionally and independently be further substituted by 1, 2 or 3substituents selected from straight and branched C₁-C₆ alkyl, NO₂, CF₃,C₁-C₆ alkoxy, chloro, fluoro, bromo, and iodo. The substitutions on thephenyl ring and on the heteroaromatic ring may take place in anyposition on said ring systems;

[0021] When the R¹ phenyl ring and the R¹ heteroaromatic ring(s) aresubstituted, the preferred substituents are selected from anyone of CF₃,methyl, iodo, bromo, fluoro and chloro.

[0022] A further embodiment of the present invention is a compoundaccording to FIG. I wherein R¹ is as defined above and each R¹ phenylring and R¹ heteroaromatic ring may independently be further substitutedby a methyl group

[0023] A further embodiment of the present invention is a compoundaccording to FIG. I wherein R¹ is phenyl, pyrrolyl, pyridinyl, thienylor furanyl, optionally with 1 or 2 of the preferred substituents on theR¹ phenyl or R¹ heteroaromatic ring.

[0024] Another embodiment of the present invention is a compoundaccording to FIG. I wherein R¹ is phenyl, pyrrolyl or pyridinyl,optionally with 1 or 2 of the preferred substituents on the R¹ phenyl orR¹ heteroaromatic ring.

[0025] Another embodiment of the present invention is a compoundaccording to FIG. I wherein R¹ is thienyl or furanyl, optionally with 1or 2 of the preferred substituents on the R¹ heteroaromatic ring.

[0026] Within the scope of the invention are also salts and enantiomersof the compounds of the formula I, including salts of enantiomers.

[0027] Reaction step b in Scheme 1, vide infra, is performed by reactingan intermediate compound of the general formula II

[0028] wherein PG is a urethane protecting group, such as Boc and CBZ,or benzyl or substituted benzyl protecting group, such as2,4-dimethoxybenzyl; with N,N-diethyl-4-bromobenzamide, using apalladium catalyst, e.g. tris(dibenzylideneacetone)dipalladium(0)-[Pd₂(dba)₃], in the presence of a base, e.g. tert-BuONaand a phosphine ligand such asbis-diphenylphosphanyl-dimethyl-9H-xanthene (xantphos), to give thecompounds of general formula III,

[0029] which is thereafter 1) deprotected, under standard conditions, 2)hydrolyzed under basic conditions and 3) alkylated using either:

[0030] i) a compound of the general formula R¹—CH₂—X, wherein R¹ is asdefined above and X is a halogen, preferably bromine or chlorine and asuitable base, or

[0031] ii) a compound of the general formula R¹—CHO, wherein R¹ is asdefined above, and a suitable reducing agent, to give compounds of thegeneral formula I.

[0032] Suitable bases to be used in the standard alkylation step i)above include, but are not limited to, triethylamine and potassiumcarbonate.

[0033] Suitable reducing agents to be used in the standard reductionstep ii) include, but are not limited to, sodium cyanoborohydride andsodium triacetoxyborohydride.

[0034] The novel compounds of the present invention are useful intherapy, especially for the treatment of various pain conditions such aschronic pain, neuropathic pain, acute pain, cancer pain, pain caused byrheumatoid arthritis, migraine, visceral pain etc. This list is shouldhowever not be interpreted as exhaustive.

[0035] Compounds of the invention are useful as irumunomodulators,especially for autoimmune diseases, such as arthritis, for skin grafts,organ transplants and similar surgical needs, for collagen diseases,various allergies, for use as anti-tumour agents and anti viral agents.

[0036] Compounds of the invention are useful in disease states wheredegeneration or dysfunction of opioid receptors is present or implicatedin that paradigm. This may involve the use of isotopically labeledversions of the compounds of the invention in diagnostic techniques andimaging applications such as positron emission tomography (PET).

[0037] Compounds of the invention are useful for the treatment ofdiarrhoea, depression, anxiety and stress-related disorders such aspost-traumatic stress disorders, panic disorder, generalized anxietydisorder, social phobia, and obesessive compulsive disorder; urinaryincontinence, various mental illnesses, cough, lung oedema, variousgastro-intestinal disorders, e.g. constipation, functionalgastrointestinal disorders such as Irritable Bowel

[0038] Syndrome and Functional Dyspepsia, Parkinson's disease and othermotor disorders, traumatic brain injury, stroke, cardioprotectionfollowing miocardial infarction, spinal injury and drug addiction,including the treatment of alcohol, nicotine, opioid and other drugabuse and for disorders of the sympathetic nervous system for examplehypertension.

[0039] Compounds of the invention are useful as an analgesic agent foruse during general anaesthesia and monitored anaesthesia care.Combinations of agents with different properties are often used toachieve a balance of effects needed to maintain the anaesthetic state(eg. amnesia, analgesia, muscle relaxation and sedation). Included inthis combination are inhaled anaesthetics, hypnotics, anxiolytics,neuromuscular blockers and opioids.

[0040] Also within the scope of the invention is the use of any of thecompounds according to the formula I above, for the manufacture of amedicament for the treatment of any of the conditions discussed above.

[0041] A further aspect of the invention is a method for the treatmentof a subject suffering from any of the conditions discussed above,whereby an effective amount of a compound according to the formula Iabove, is administered to a patient in need of such treatment.

[0042] A further aspect of the present invention is intermediates of thegeneral formula II and III,

[0043] wherein PG is a urethane protecting group, such as Boc and CBZ orbenzyl or substituted benzyl protecting group, such as2,4-dimethoxybenzyl.

[0044] A further embodiment of the present invention is intermediates ofthe Formula X

[0045] wherein R¹ is as described above in relation to Formula I.

[0046] In another alternative synthetic route, reaction step b in Scheme2, vide infra, is performed by reacting an intermediate compound of thegeneral formula IV

[0047] wherein PG is a urethane or benzyl-like protecting group, such asBoc, N,N-diethyl-4-bromobenzamide, using a palladium catalyst, e.g.tris(dibenzylideneacetone) dipalladium(0) [Pd₂(dba)₃], in the presenceof a base, e.g. tert-BuONa and a phosphine ligand such asbis-diphenylphosphanyl-dimethyl-9H-xanthene (xantphos), to give the iscompounds of general formula V,

[0048] which is thereafter 1) deprotected, under standard conditions, 2)hydrolyzed under basic conditions and 3) alkylated using either:

[0049] i) a compound of the general formula R¹—CH₂—X, wherein R¹ is asdefined above and X is a halogen, preferably bromine or chlorine and asuitable base, or

[0050] ii) a compound of the general formula R¹—CHO, wherein R¹ is asdefined above, and a suitable reducing agent, to give compounds of thegeneral formula I.

[0051] This is followed by conversion of the ketal functionality to aprimary amide under standard conditions via 1) hydrolysis of the ketalto the aldehyde (formula VI), followed by 2) oxidation of the aldehydeto the corresponding carboxylic acid (formula VII), followed by 3)amidation with ammonium chloride to the primary amide giving compoundsof the general formula I.

[0052] Suitable hydrolysis conditions to be used in the standardhydrolysis step (i) include, but are not limited to aqueous hydrochloricacid in tetrahydrofuran.

[0053] Suitable conditions for the oxidation step (ii) include, but arenot limited to stirring at 0° C. in aqueous sodium dihydrogen phosphateand sodium chlorite in the presence of excess 2-methyl-2-butene.

[0054] Suitable conditions for the amidation step (iii) include but arenot limited to treatment with excess ammonium chloride in the presenceof a coupling agent such as benzotriazole-1-yloxy-trisphosphoniumhexafluorophosphate (hereinafter Py-BOP).

Methods of Preparation EXAMPLES

[0055] The invention will now be described in more detail by thefollowing Schemes and Examples, which are not to be construed aslimiting the invention.

[0056] Method 1A (Compound 1):3-(1-Benzyl-piperidin-4-ylamino)-4-fluoro-benzonitrile

[0057] To a dry flask containing 3-bromo-4-fluoro benzonitrile (6.56 g,1 eq) was added dry toluene (100 mL), 4-amino-1-benzyl piperidine(1.2eq), racemic BINAP (612 mg, 0.03 eq), palladium acetate (220 mg,0.02 eq) and sodium tert-butoxide (4.4 g, 1.4 eq). The reaction washeated to 80° C. under and inert atmosphere for 20 hours . The reactionwas cooled, diluted with ethyl acetate (200 mL) and washed with water(110 mL). The combined organics were dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography, eluting 3% methanolin dichloromethane yielded amine (1) as a yellow solid (6.655 g, 66%).

[0058] Method 1B (Compound 2):[(1-Benzyl-piperidin-4-yl)-(5-cyano-2-fluoro-phenyl)-amino]-N,N-diethyl-benzamide.

[0059] To a solution of amine (1) (3.50 g, leq.) in dry toluene (50 mL)was added aryl bromide (4.35 g, 1.5 eq), xantphos (393 mg, 0.06 eq),Pd₂(dba)₃ (331 mg, 0.03 eq) and sodium tert-butoxide (1.52 g, 1.4 eq).The reaction was heated to reflux for 14 hours then was cooled anddiluted with ethyl acetate (100 mL). The solution was washed with water(100 mL) then the organics were dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography, eluting 65% ethylacetate 35% hexanes, rising to 70% ethyl acetate 30% hexanes yieldedamine (2) as an orange oil (3.568 g, 65% yield).

[0060] Method 1C (Compound 3):[(5-Cyano-2-fluoro-phenyl)-piperidin-4-yl-amino]-N,N-diethyl-benzamide.

[0061] To a solution of amine (2) (3.564 g, 1 eq) in 1,2-dichloroethane(65 mL) at 0° C. was added 1-chloroethyl chloroformate (920 μL, 1.15eq). After 1 hour at 0° C. the reaction was warmed to room temperaturethen was heated to 70° C. for 90 minutes. The reaction was then cooledand concentrated. The residue was dissolved in methanol (60 mL) thenheated to 70° C. for 1 hour. The solution was then cooled andconcentrated. Purification by flash chromatography, eluting 10% methanolin dichloromethane, rising to 40% methanol in dichloromethane gave amineas a yellow foam (2.786 g, 96%).

[0062] Intermediate 4:(1-Benzyl-piperidin-4-yl)-(5-[1,3]dioxolan-2-yl-2-fluoro-phenyl)-amine.

[0063] To a dry flask containing2-(3-bromo-4-fluorophenyl)-1,3-dioxaolane (1.0 eq) and amine, (1.2 eq)in dry toluene is added BINAP (0.03 eq), palladium acetate (0.02 eq) andsodium tert-butoxide (1.4 eq). The reaction is heated to 80° C. undernitrogen. After about 24 hours the solution is cooled, diluted withethyl acetate and washed with one portion water. The organics are driedover anhydrous magnesium sulfate, filtered and concentrated. The residueis purified by flash chromatography, eluting with a methanol indichloromethane gradient.

[0064] Intermediate 5:[(1-Benzyl-piperidin-4-yl)-(5-[1,3]dioxolan-2-yl-2-fluoro-phenyl)-amino]-N,N-diethyl-benzamide.

[0065] To a dry flask containing amine 4 in dry toluene (about 6 mL permillimole of 4) is added aryl bromide (1.4 eq), xantphos (0.06 eq),Pd₂(dba)₃ (0.03 eq) and sodium tert-butoxide (1.4 eq). The reaction isheated to 110° C. under nitrogen. After about 24 hours the solution iscooled, diluted with ethyl acetate and washed with one portion water.The organics are dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue is purified by flash chromatography, elutingwith a methanol in dichloromethane gradient.

[0066] Intermediate 6:[(1-Benzyl-piperidin-4-yl)-(2-fluoro-5-formyl-phenyl)-amino]-N,N-diethyl-benzamide.

[0067] To a solution of acetal 5 in tetrahydrofuran is added 2N HClsolution (2.0 eq). After 16 hours at room temperature, dichloromethaneis added and the aqueous layer is neutralized with aqueous saturatedsodium bicarbonate solution. The organic layer is removed and theaqueous layer extracted with two portions of dichloromethane. Thecombined organic extracts are dried (MgSO₄), filtered and concentratedand the residue is purified by flash chromatography, eluting with anethyl acetate in hexanes gradient.

[0068] Intermediate 7:[(1-Benzyl-piperidin-4-yl)-(4-diethylcarbamoyl-phenyl)-amino]-4-fluoro-benzoicacid.

[0069] To a solution of aldehyde 6 (1.0 eq) in tert-butanol is added2-methyl-2-butene (10.0 eq) and the solution is cooled to 0° C. Asolution of sodium dihydrogen phosphate (9 eq) and sodium chlorite (9eq) in water is added and the reaction is stirred for 30 minutes at 0°C. The tert-butanol is removed and the reaction mixture is extractedwith dichloromethane. The combined organic extracts are dried (MgSO₄),filtered and concentrated and the residue is purified by flashchromatography, eluting with a methanol/dichloromethane gradient.

Example 1[(1-Benzyl-piperidin-4-yl)-(4-diethylcarbamoyl-phenyl)-amino]4-fluoro-benzamide(Alternative Synthesis).

[0070] To a solution of acid 7 (1.0 eq) in DME is added pyBOP (1.5 eq);HOBt (1.5 eq), diisopropyIethylarnine (4.0 eq) and ammonium chloride (2eq). After 16-24 hours at room temperature the reaction is concentrated.The residue is dissolved in ethyl acetate and is washed with twoportions of water and one portion of saturated sodium bicarbonatesolution. The organic layer is dried (MgSO₄), filtered and concentratedand the residue is purified by flash chromatography, eluting with amethanol in dichloromethane gradient.

[0071] Additional examples were synthesized via the general proceduresdescribed below.

[0072] A. Reductive amination of intermediate 3:

[0073] To a solution of the amine, 3 in dry tetrahydrofuran (THF) or1,2-dichloroethane is added the aldehyde (1-1.5 eq.), followed by sodiumtriacetoxyborohydride (1-1.6 eq.). The reaction is stirred at roomtemperature under a nitrogen atmosphere for an extended period of time(6-48 hours) to ensure complete reaction. The reaction mixture is thensubjected to a standard work-up procedure and a standard purification.The amount of THF or 1,2-dichloroethane is not crucial. An amountcorresponding to about 1 mL/30 mg is preferred.

[0074] Procedure 2A in the synthesis of Example 2 below is typical.

[0075] B. Hydrolysis of the Intermediate Cyano Compound:

[0076] To a solution of the cyano intermediate in tert-butanol, is addedground potassium hydroxide (KOH) (2.5 eq.) and the resulting mixture isheated to reflux for about two hours. The mixture was then cooled toroom temperature and subjected to a standard work-up procedure and astandard purification. The amount of tert-butanol is not crucial. Anamount corresponding to about 1 mL/30 mg is preferred. Procedure 2B inthe synthesis of Example 2 below is typical.

Example 2[(4-Diethylcarbamoyl-phenyl)-(1-pyridin-2-ylmethyl-piperidin-4-yl)-amnino]-4-fluoro-benzamide.

[0077]

[0078] 2A:[(5-Cyano-2-fluoro-phenyl)-(1-pyridin-2-ylmethyl-piperidin-4-yl)-amino]-N,N-diethyl-benzamide.

[0079] To a solution of amine (370 mg) in dry tetrahydrofuran (10 mL)was added pyridine-2-carboxaldehyde (116 μL; 1.3 eq) and sodiumtriacetoxyborohydride (279 mg; 1.4 eq). The reaction was stirred at roomtemperature under nitrogen. After 24 hours the reaction was diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate.The aqueous was extracted with two portions dichloromethane and thecombined organics were dried over anhydrous magnesium sulfate, filteredand concentrated. The residue was purified by flash chromatographyeluting 4% methanol in dichloromethane. A colorless foam was obtained(317.5 mg; 70% yield.).

[0080] 2B: [(4-Diethylcarbamoyl-phenyl)-(4l-pyridin-2-ylmethyl-piperidin-4-yl)-amino]-4-fluoro-benzamide.

[0081] To a solution of nitrile (317 mg) in tert-butanol (10 mL) wasadded ground potassium hydroxide (92 mg; 2.5 eq) and the reaction washeated to reflux. After 90 minutes the solution was cooled, diluted withdichloromethane and washed with one portion water. The organics wasremoved and the aqueous neutralized with 2M hydrochloric acid andextracted with two portions dichloromethane. The combined organics weredried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography eluting with 5% methanol indichloromethane, rising to 7% methanol in dichloromethane. A colorlessfoam was obtained (164.0 mg; 50% yield). The foam was dissolved in ether(8 mL) containing some dichloromethane and 1N HCl/ether (1.0 mL; ≅3.0eq) was added After 1 hour the solution was concentrated and the soliddried under high vacuum.

[0082] Additional Examples are prepared analogously. Analytical data forsynthetic Examples is shown in Table 1, on the following pages. TABLE 1Analytical data for synthetic Examples Ex. # R¹ Name NMR data(400 MHz,CD₃OD) 1

[(1-Benzyl-piperidin- 4-yl)-(4-diethyl- carbamoyl-phenyl)-amino]-fluoro- benzamide (1.19(br s, 6H, CH₃); 1.69-1.80(m, 2H, CH₂);2.31(d, J=14 Hz, 2H, CH₂); 3.25-3.55(m, 3H, NCH₂); 4.31(s, 2H, NCH₂Ar);4.42-4.49 (m, 1H, NCH); 6.70(d, J=9Hz, 2H, Ar—H); 7.26(d, J=9 Hz, 2H,Ar—H); 7.38-7.42(m, 1H, Ar—H); 7.47-7.51(m, 5H, Ar—H); 7.83(dd, J=3, 7.5Hz, 1H, Ar—H); 7.99-8.03(m, 1H, #Ar—H). 2

[(4-Diethylcarbamoyl- phenyl)-(1-pyridin-2- ylmethyl-piperidin-4-yl)-amino]-fluoro- benzamide 1.17(br s, 6H, CH3); 1.81-1.85(m, 2H, CH₂);2.31(d, J=14 Hz, 2H, CH₂); 3.36-3.42(m, 6H, NCH₂); 3.63(d, J=12 Hz, 2H,NCH₂); 4.48-4.52(m, 3H, NCH2 and NCH); 6.70(d, J=8.5 Hz, 2H, Ar—H);7.26(d, J=8.5 Hz, 2H, Ar—H); 7.41(t, J=8.5 Hz, 1H, Ar—H); 7.51-7.54(m,1H, Ar—H); 7.60(d, J=7.5 Hz, 1H, #Ar—H); 7.84-7.86(m, 1H, Ar—H);7.98-8.01 (m, 2H, Ar—H); 8.68(d, J=6.5 Hz, 1H, Ar—H). 3

[(4- Diethylcarbamoyl- phenyl)-(1-thiophen-3- ylmethyl-piperidin-4-yl)-amino]-fluoro- benzamide 1.16(br s, 6H, CH3); 1.63-1.74(m, 2H, CH₂);2.31(d, J=14 Hz, 2H, CH₂); 3.19∝3.25(m, 2H, NCH₂); 3.40(br s, 4H, NCH2);3.52(d, J=13 Hz, 2H, NCH₂); 4.31(s, 2H, NCH₂Ar); 4.36-4.45(m, 1H, NCH);6.67(d, J=9.5Hz, 2H, Ar—H); 7.18-7.27(m, 3H, Ar—H); 7.38(t, J=9 Hz, 1H,Ar—H); 7.54-7.56(m, 1H, Ar— #H); 7.65-7.66(m, 1H, Ar—H); 7.81(dd, J=2,7.5 Hz, 1H, Ar—H); 7.97-8.01(m, 1H, Ar—H). 4

[(4-Diethylcarbamoyl- phenyl)-(1-furan-3- ylmethyl-piperidin-4-yl)-amino]-fluoro- benzamide 1.16(br s, 6H, CH₃); 1.57-1.67(m, 2H, CH₂);2.32(d, J=14 Hz, 2H, CH₂); 3.17-3.23(m, 2H, NCH₂); 3.42(br s, 4H, NCH₂);3.56(d, J=12 Hz, 2H, NCH₂); 4.18(s, 2H, NCH₂Ar); 4.39-4.45(m, 1H, NCH);6.56(s, 1H, Ar—H); 6.67(d, J=9.5 Hz, 2H, Ar—H); 7.23-7.27(m, 2H, Ar—H);7.39(t, J=9.5 Hz, 1H, #Ar—H); 7.81(dd, J=2.5, 7.5 Hz, 1H, Ar—H);7.97-8.01 (m, 1H, Ar—H) 5

[(4-Diethylcarbamoyl- phenyl)-(1-thiophen-2- ylmethyl-piperidin-4-yl)-amino]-fluoro- benzamide 1.16(br s, 6H, CH₃); 1.63-1.74(m, 2H, CH₂);2.33(d, J=14 Hz, 2H, CH₂); 3.24(t, J=11 Hz, 2H, NCH₂); 3.40(br s, 4H,_(NCH2)); 3.57(d, J=12 Hz, 2H, NCH2); 4.39-4.45(m, 1H, NCH); 4.54(s, 2H,NCH₂Ar); 6.67(d, J=9.5 Hz, 2H, Ar—H); 7.11-7.13(m, 1H, Ar—H);7.22-7.26(m, 2H, Ar—H); 7.31(d, J=3.5 #Hz, 1H, Ar—H); 7.39(t, J=9.5 Hz,1H, Ar—H); 7.61(d, J=6.5 Hz, 1H, Ar—H); 7.80-7.82(m, 1H, Ar—H);7.97-8.01(m, 1H, Ar—H). 6

[[1-(2,4-Dichloro- benzyl)-piperidin-4- yl]-(4-diethylcarbam-oyl-phenyl)-amino]- fluoro-benzamide 1.16(br s, 6H, CH₃); 1.67-1.77(m,2H, CH₂); 2.31(d, J=14 Hz, 2H, CH₂); 3.30-3.50(m, 6H, NCH₂); 3.59(d,J=12 Hz, 2H, NCH₂); 4.42-4.48(m, 3H, NCH and NCH₂Ar); 6.67 (d, J=9.5 Hz,2H, Ar—H); 7.23(d, J=8.5 Hz, 2H, Ar—H); 7.38(t, J=9.5 Hz, 1H, Ar—H);7.45-7.48(m, 1H, Ar—H); 7.59(d, #J=8.5 Hz, 1H, Ar—H); 7.66(d, J=2 Hz,1H, Ar—H); 7.80 (J=2, 7.5 Hz, 1H, Ar—H); 7.96-8.00(m, 1H, Ar—H). 7

[(Diethylcarbamoyl- phenyl)-(1-thiazol-2- ylmethyl-piperidin-4-yl)-amino]-fluoro- benzamide 1.16(br s, 6H, CH₃); 1.77-1.82(m, 2H, CH₂);2.33(d, J=14 Hz, 2H, CH₂); 3.40-3.53(m, 6H, NCH₂); 3.71(d, J=11 Hz, 2H,NCH₂); 4.48-4.53(m, 1H, NCH); 4.73(s, 2H, NCH₂Ar); 6.73(d, J=8.5 Hz, 2H,Ar—H); 7.30 (d, J=8.5 Hz, 2H, Ar—H); 7.39-7.43(m, 1H, Ar—H); 7.77(d, J=3Hz, 1H, Ar—H); 7.84(d, # J=5.5 Hz, 1H, Ar—H); 7.93(d, J=3Hz, 1H, Ar—H);8.00-8.04(m, 1H, Ar—H). 8

[[1-(4-Bromo-benzyl)- piperidin-4-yl]-(4- diethylcarbamoyl-phenyl)-amino]- fluoro-benzamide 1.16(br s, 6H, CH₃); 1.64-1.75(m, 2H,CH₂); 2.30(d, J=14 Hz, 2H, CH2); 3.22-3.28(m, 2H, NCH₂); 3.42-3.53(m,6H, NCH₂); 4.27 (s, 2H, NCH₂Ar); 4.38-4.46(m, 1H, NCH); 6.67(d, J=8.5Hz, 2H, Ar—H); 7.24(d, J=8.5 Hz, 2H, Ar—H); 7.36-7.41(m, 3H, Ar—H);7.63(d, J=8.5 Hz, 2H, Ar—H); 7.80(dd, #J=2, 7.5 Hz, 1H, Ar—H);7.97-8.00(m, 1H, Ar—H). 9

[(4-Diethylcarbamoyl- phenyl)-(1-furan-2- ylmethyl-piperidin-4-yl)-amino]-fluoro- benzamide 1.16(br s, 6H, CH₃); 1.63-1.73(m, 2H, CH₂);2.32(d, J=14 Hz, 2H, CH₂); 3.22-3.48(m, 6H, NCH₂); 3.53(d, J=13 Hz, 2H,NCH₂); 4.37(s, 2H, NCH₂Ar); 4.39-4.44(m, 1H, NCH); 6.50-6.52(m, 1H,Ar—H); 6.65-6.70 (m, 3H, Ar—H); 7.21(d, J=3 Hz, 2H, Ar—H); 7.39(t, J=9.5Hz, 1H, Ar—H); 7.65(s, 1H, Ar— #H); 7.81(dd, J=2, 7.5 Hz, 1H, Ar—H);7.90-8.01(m, 1H, Ar—H). 10

[(4-Diethylcarbamoyl- phenyl)-(1-pyridin-4- ylmethyl-piperidin-4-yl)-amino]-fluoro- benzamide 1.16(br s, 6H, CH₃); 1.85-1.94(m, 2H, CH₂);2.31(d, J=13 Hz, 2H, CH₂); 3.30-3.48(m, 6H, NCH₂); 3.60(d, J=11Hz, 2H,NCH₂); 4.45-4.51(m, 1H, NCH); 4.68(s, 2H, NCH₂Ar); 6.69(d, J=8.5 Hz, 2H,Ar—H); 7.24 (d, J=9.5 Hz, 2H, Ar—H); 7.38(t, J=9.5 Hz, 1H, Ar—H);7.82(d, J=6.5 Hz, 1H, Ar—H); #7.97-8.01(m, 1H, Ar—H); 8.32(d, J=7.5 Hz,2H, Ar—H); 8.98(d, J=6.5 Hz, 2H, Ar—H). 11

[[1-(4-Chloro- benzyl)-piperidin-4- yl]-(4-diethyl- carbamoyl-phenyl)-amino]-fluoro- benzamide 1.14(br s, 6H, CH₃); 1.62-1.73(m, 2H, CH₂);2.28(d, J=15 Hz, 2H, CH₂); 3.23(t, J=13 Hz, 2H, NCH₂); 3.39(br s, 4H,NCH₂); 3.50(d, J=13 Hz, 2H, NCH₂); 4.26(s, 2H, NCH₂Ar); 4.36-4.44(m, 1H,NCH); 6.64(d, J=8.5 Hz, 2H, Ar—H); 7.20(d, J=9.5 Hz, 2H, Ar—H); 7.36 (t,J=9.5 Hz, 1H, Ar #—H); 7.42-7.47(m, 4H, Ar—H); 7.78(dd, J=2, 7.5 Hz, 1H,Ar—H); 7.94-7.98(m, 1H, Ar—H). 12

[(4- Diethylcarbamoyl- phenyl)-(1-pyridin-3- ylmethyl-piperidin-4-yl)-amino]-fluoro- benzamide 1.15(br s, 6H, CH₃); 1.80(q, J=12 Hz, 2H,CH₂); 2.29(d, J=14 Hz, 2H, CH₂); 3.35-3.47 (m, 6H, NCH₂); 3.60(d, J=12Hz, 2H, NCH₂); 4.42-4.49(m, 1H, NCH); 4.60(s, 2H, NCH₂Ar); 6.66(d, J=8.5Hz, 2H, Ar—H); 7.22 (d, J=8.5 Hz, 2H, Ar—H); 7.35(t, J=9.5 Hz, 1H,Ar—H); 7.79(d, J=6.5 Hz, 1H, #Ar—H); 7.94-7.98(m, 1H, Ar—H);8.11-8.15(m, 1H, Ar—H); 8.78 (d, J=8.5 Hz, 1H, Ar—H); 8.94(d, J=5.5 Hz,1H, Ar—H); 9.14(s, 1H, Ar—H). 13

{(4- Diethylcarbamoyl- phenyl)-[1-(3H- imidazol-4- ylmethyl)-piperidin-4-yl]-amino}-fluoro- benzamide 1.14(br s, 6H, CH₃); 1.79-1.85(m, 2H,CH₂); 2.31(d, J=14 Hz, 2H, CH₂); 3.32-3.46(m, 6H, NCH₂); 3.60(d, J=11Hz, 2H, NCH₂); 4.41-4.47(m, 1H, NCH); 4.50(s, 2H, NCH₂Ar); 6.67(d, J=9.5Hz, 2H, Ar—H); 7.22(d, J=8.5 Hz, 2H, Ar—H); 7.36(t, J=9.5 Hz, 1H, Ar—H);7.80 (d, J= #5.5 Hz, 1H, Ar—H); 7.86(s, 1H, Ar—H); 7.95-7.99(m, 1H,Ar—H); 9.05(d, J=2 Hz, 1H, Ar—H). 14

{(4- Diethylcarbamoyl- phenyl)-[1-(1H- imidazol-2- ylmethyl)-piperidin-4-yl]-amino}-fluoro- benzamide 1.14(br s, 6H, CH₃); 1.79-1.85(m, 2H,CH₂); 2.31(d, J=14 Hz, 2H, CH₂); 3.32-3.46(m, 6H, NCH₂); 3.60(d, J=11Hz, 2H, NCH₂); 4.41-4.47(m, 1H, NCH); 4.50(s, 2H, NCH₂Ar); 6.67(d, J=9.5Hz, 2H, Ar—H); 7.22(d, J=8.5 Hz, 2H, Ar—H); 7.36(t, J=9.5 Hz, 1H, Ar—H);7.80 (d, J= #5.5 Hz, 1H, Ar—H); 7.86(s, 1H, Ar—H); 7.95-7.99(m, 1H,Ar—H); 9.05(d, J=2 Hz, 1H, Ar—H). 15

{(4- Diethylcarbamoyl- phenyl)-[1-(1H- pyrrol-2-ylmethyl)-piperidin-4-yl]- amino}-fluoro- benzamide 1.13(br s, 6H, CH₃);1.58-1.69(m, 2H, CH₂); 2.29(d, J=13 Hz, 2H, CH₂); 3.10(d, J=11 Hz, 1H,NCH); 3.14(d, J=11Hz, 1H, NCH); 3.38 (br s, 4H, NCH₂); 3.47(d, J=13 Hz,2H, NCH₂); 4.21(s, 2H, _(NCH2Ar)); 4.31-4.39(m, 1H, NCH); 6.12(m, 1H,Ar—H); 6.29(s, 1H, Ar—H); 6.63 (d, J=8.5 Hz, #2H, Ar—H); 6.83-6.84(m,1H, Ar—H); 7.20(d, J=9 Hz, 2H, Ar—H); 7.35(t, J=9.5 Hz, 1H, Ar—H);7.77-7.79(m, 1H, Ar—H); 7.94-7.98(m, 1H, Ar—H); 10.60(br s, 1H, NH)

Pharmaceutical Compositions

[0083] The novel compounds according to the present invention may beadministered orally, sublingually, intramuscularly, subcutaneously,topically, intranasally, intraperitoneally, intrathoracially,intravenously, epidurally, intrathecally, intracerebroventricularly andby injection into the joints.

[0084] A preferred route of administration is orally, intravenously orintramuscularly. The dosage will depend on the route of administration,the severity of the disease, age and weight of the patient and otherfactors normally considered by the attending physician, when determiningthe individual regimen and dosage level as the most appropriate for aparticular patient.

[0085] For preparing pharmaceutical compositions from the compounds ofthis invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, and suppositories.

[0086] A solid carrier can be one or more substances which may also actas diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, or tablet disintegrating agents; it can also be anencapsulating material.

[0087] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

[0088] For preparing suppository compositions, a low-melting wax such asa mixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

[0089] Suitable carriers are magnesium carbonate, magnesium stearate,talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoabutter, and the like.

[0090] Salts include, but are not limited to, pharmaceuticallyacceptable salts. Examples of pharmaceutically acceptable salts withinthe scope of the present invention include: acetate, benzenesulfonate,benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glucaptate, gluconate, glutaniate,glycollylarsamilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, isethionate, lactate, lactobionate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, pamoate (embonate),pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate,triethiodide, and benzathine.

[0091] Examples of pharmaceutically unacceptable salts within the scopeof the present invention include: hydroiodide, perchlorate,tetrafluoroborate. Pharmaceutically unacceptable salts could be of usebecause of their advantageous physical and/or chemical properties, suchas crystallinity.

[0092] Preferred pharmaceutically acceptable salts are hydrochlorides,sulfates and bitartrates. The hydrochloride and sulfate salts areparticularly preferred.

[0093] The term composition is intended to include the formulation ofthe active component with encapsulating material as a carrier providinga capsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

[0094] Tablets, powders, cachets, and capsules can be used as soliddosage forms suitable for oral administration.

[0095] Liquid from compositions include solutions, suspensions, andemulsions. Sterile water or water-propylene glycol solutions of theactive compounds may be mentioned as an example of liquid preparationssuitable for parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution.

[0096] Aqueous solutions for oral administration can be prepared bydissolving the active component in water and adding suitable colorants,flavoring agents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

[0097] Preferably the pharmaceutical compositions is in unit dosageform. In such form, the composition is divided into unit dosescontaining appropriate quantities of the active component. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of the preparations, for example, packeted tablets,capsules, and powders in vials or ampoules. The unit dosage form canalso be a capsule, cachet, or tablet itself, or it can be theappropriate number of any of these packaged forms.

BIOLOGICAL EVALUATION In Vitro Model Cell Culture

[0098] A. Human 293S cells expressing cloned human μ, δ, and κ receptorsand neomycin resistance were grown in suspension at 37° C. and 5% CO₂ inshaker flasks containing calcium-free DMEM10% FBS, 5% BCS, 0.1% PluronicF-68, and 600 μg/mnl geneticin.

[0099] B. B. Mouse and rat brains were weighed and rinsed in ice-coldPBS (containing 2.5 mM EDTA, pH 7.4). The brains were homogenized with apolytron for 15 sec (mouse) or 30 sec (rate in ice-cold lysis buffer (50mM Tris, pH 7.0, 2.5 mM EDTA, with phenylmethylsulfonyl fluoride addedjust prior use to 0.5 MmM from a 0.5M stock in DMSO:ethanol).

[0100] Membrane Preparation

[0101] Cells were pelleted and resuspended in lysis buffer (50 mM Tris,pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a0.1 M stock in ethanol), incubated on ice for 15 min, then homogenizedwith a polytron for 30 sec. The suspension was spun at 1000 g (max) for10 min at 4° C. The supernatant was saved on ice and the pelletsresuspended and spun as before. The supernatants from both spins werecombined and spun at 46,000 g(rax) for 30 min. The pellets wereresuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again.The final pellets were resuspended in membrane buffer (50 mM Tris, 0.32M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozenin dry ice/ethanol and stored at −70° C. until use. The proteinconcentrations were determined by a modified Lowry assay with SDS.

[0102] Binding Assays

[0103] Membranes were thawed at 37° C., cooled on ice, passed 3 timesthrough a 25-gauge needle, and diluted into binding buffer (50 mM Tris,3 mM MgCl₂, 1 mg/ml BSA (Sigma A-7888), pH 7.4, which was stored at 4°C. after filtration through a 0.22 m filter, and to which had beenfreshly added 5 μ/ml aprotinin, 10 μm bestatin, 10 μm diprotin A, noDTT). Aliquots of 100 μl were added to iced 12×75 mm polypropylene tubescontaining 100 μl of the appropriate radioligand and 100 μl of testcompound at various concentrations. Total (TB) and nonspecific (NS)binding were determined in the absence and presence of 10 μM naloxonerespectively. The tubes were vortexed and incubated at 25° C. for 60-75min, after which time the contents are rapidly vacuum-filtered andwashed with about 12 ml/tube iced wash buffer (50 mM Tris, pH 7.0, 3 mMMgCl₂) through GF/B filters (Whatman) presoaked for at least 2 h in 0.1%polyethyleneimine. The radioactivity (dpm) retained on the filters wasmeasured with a beta counter after soaking the filters for at least 12 hin minivials containing 6-7 ml scintillation fluid. If the assay is setup in 96-place deep well plates, the filtration is over 96-placePEI-soaked unifilters, which were washed with 3×1 ml wash buffer, anddried in an oven at 55° C. for 2 h. The filter plates were counted in aTopCount (Packard) after adding 50 μl MS-20 scintillation fluid/well.

[0104] Functional Assays

[0105] The agonist activity of the compounds is measured by determiningthe degree to which the compounds receptor complex activates the bindingof GTP to G-proteins to which the 15 receptors are coupled. In the GTPbinding assay, GTP[γ]³⁵S is combined with test compounds and membranesfrom HEK-293S cells expressing the cloned human opioid receptors or fromhomogenised rat and mouse brain. Agonists stimulate GTP[γ]³⁵S binding inthese membranes. The EC₅₀ and E_(max) values of compounds are determinedfrom dose-response curves. Right shifts of the dose response curve bythe delta antagonist naltrindole are performed to verify that agonistactivity is mediated through delta receptors.

[0106] Procedure for Rat Brain GTP

[0107] Rat brain membranes are thawed at 37° C., passed 3 times througha 25-gauge blunt-end needle and diluted in the GTPγS binding (50 mMHepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl₂, pH 7.4, Addfresh: 1 mM DTT, 0.1% BSA). 120 μM GDP final is added membranesdilutions. The EC₅₀ and E_(max) of compounds are evaluated from 10-pointdose-response curves done in 300 μl with the appropriate amount ofmembrane protein (20 μg/well) and 100000-130000 dpm of GTPγ³⁵S per well(0.11-0.14 nM). The basal and maximal stimulated binding are determinedin absence and presence of 3 μM SNC-80

[0108] Data Analysis

[0109] The specific binding (SB) was calculated as TB-NS, and the SB inthe presence of various test compounds was expressed as percentage ofcontrol SB. Values of IC₅₀ and Hill coefficient (n_(H)) for ligands indisplacing specifically bound radioligand were calculated from logitplots or curve fitting programs such as Ligand, Graph Pad Prism,SigmaPlot, or ReceptorFit. Values of K_(i) were calculated from theCheng-Prussoff equation. Mean±S.E.M. values of IC₅₀, K_(i) and n_(H)were reported for ligands tested in at least three displacement curves.Biological activity of the compounds of the present invention isindicated in Table 2. TABLE 2 Biological data. HDELTA RAT BRAIN MOUSEBRAIN (nM) (nM) (nM) Ex. # IC₅₀ EC₅₀ % EMax EC₅₀ % EMax EC₅₀ % EMax 1-150.247-5.405 0.115-338.89 84.69-110.25 0.563-73.672 100.1-176.860.807-48.164 93.36-163.19

[0110] Receptor Saturation Experiments

[0111] Radioligand K_(δ) values were determined by performing thebinding assays on cell membranes with the appropriate radioligands atconcentrations ranging from 0.2 to 5 times the estimated K₆₇ (up to 10times if amounts of radioligand required are feasible). The specificradioligand binding was expressed as pmole/mg membrane protein. Valuesof K_(δ) and B_(max) from individual experiments were obtained fromnonlinear fits of specifically bound (B) vs. nM free (F) radioligandfrom individual according to a one-site model.

[0112] Determination of Mechano-Allodynia Using Von Frey Testing

[0113] Testing was performed between 08:00 and 16:00 h using the methoddescribed by Chaplan et al. (1994). Rats were placed in Plexiglas cageson top of a wire mesh bottom which allowed access to the paw, and wereleft to habituate for 10-15 min. The area tested was the mid-plantarleft hind paw, avoiding the less sensitive foot pads. The paw wastouched with a series of 8 Von Frey hairs with logarithmicallyincremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and15.14 grams; Stoelting, Ill, USA). The von Frey hair was applied fromunderneath the mesh floor perpendicular to the plantar surface withsufficient force to cause a slight buckling against the paw, and heldfor approximately 6-8 seconds. A positive response was noted if the pawwas sharply withdrawn. Flinching immediately upon removal of the hairwas also considered a positive response. Ambulation was considered anambiguous response, and in such cases the stimulus was repeated.

[0114] Testing Protocol

[0115] The animals were tested on postoperative day 1 for theFCA-treated group. The 50% withdrawal threshold was determined using theup-down method of Dixon (1980). Testing was started with the 2.04 ghair, in the middle of the series. Stimuli were always presented in aconsecutive way, whether ascending or descending. In the absence of apaw withdrawal response to the initially selected hair, a strongerstimulus was presented; in the event of paw withdrawal, the next weakerstimulus was chosen. Optimal threshold calculation by this methodrequires 6 responses in the immediate vicinity of the 50% threshold, andcounting of these 6 responses began when the first change in responseoccurred, e.g. the threshold was first crossed. In cases wherethresholds fell outside the range of stimuli, values of 15.14 (normalsensitivity) or 0.41 (maximally allodynic) were respectively assigned.The resulting pattern of positive and negative responses was tabulatedusing the convention, X=no withdrawal; O=withdrawal, and the 50%withdrawal threshold was interpolated using the formula:

50% g threshold=10^((Xf+kδ))/10,000

[0116] where Xf=value of the last von Frey hair used (log units);k=tabular value (from Chaplan et al. (1994)) for the pattern ofpositive/negative responses; and δ=mean difference between stimuli (logunits). Here δ=0.224.

[0117] Von Frey thresholds were converted to percent of maximum possibleeffect (% MPE), according to Chaplan et al. 1994. The following equationwas used to compute % MPE:$\text{\% MPE} = {\frac{\text{Drug treated threshold (g)} - \text{allodynia threshold (g)}}{\text{Control threshold (g)} - \text{allodynia threshold (g)}} \times 100}$

[0118] Administration of Test Substance

[0119] Rats were injected (subcutaneously, intraperitoneally,intravenously or orally) with a test substance prior to von Freytesting, the time between administration of test compound and the vonFrey test varied depending upon the nature of the test compound.

[0120] Writting Test

[0121] Acetic acid will bring abdominal contractions when administeredintraperitoneally in mice. These will then extend their body in atypical pattern When analgesic drugs are administered, this describedmovement is less frequently observed and the drug selected as apotential good candidate.

[0122] A complete and typical Writhing reflex is considered only whenthe following elements are present: the animal is not in movement; thelower back is slightly depressed; the plantar aspect of both paws isobservable. In this assay, compounds of the present inventiondemonstrate significant inhibition of writhing responses after oraldosing of 1-100 μmol/kg.

[0123] (i) Solutions Preparation

[0124] Acetic acid (AcOH): 120 μL of Acetic Acid is added to 19.88 ml ofdistilled water in order to obtain a final volume of 20 ml with a finalconcentration of 0.6% AcOH. The solution is then mixed (vortex) andready for injection.

[0125] Compound (drug): Each compound is prepared and dissolved in themost suitable vehicle according to standard procedures.

[0126] (ii) Solutions Administration

[0127] The compound (drug) is administered orally, intraperitoneally(i.p.), subcutaneously (s.c.) or intravenously (i.v.)) at 10 ml/lkg(considering the average mice body weight) 20, 30 or 40 minutes(according to the class of compound and its characteristics) prior totesting. When the compound is delivered centrally: Intraventricularly(i.c.v.) or intrathecally (i.t.) a volume of 5 μL is administered.

[0128] The AcOH is administered intraperitoneally (i.p.) in two sites at10 ml/kg (considering the average mice body weight) immediately prior totesting.

[0129] (iii) Testing

[0130] The animal (mouse) is observed for a period of 20 minutes and thenumber of occasions (Writhing reflex) noted and compiled at the end ofthe experiment. Mice are kept in individual “shoe box” cages withcontact bedding. A total of 4 mice are usually observed at the sametime: one control and three doses of drug.

[0131] For the anxiety and anxiety-like indications, efficacy has beenestablished in the geller-seifter conflict test in the rat.

[0132] For the functional gastrointestina disorder indication, efficacycan be established in the assay described by Coutinho S V et al, inAmerican Journal of Physiology—Gastrointestinal & Liver Physiology.282(2):G307-16, 2002 February, in the rat.

1. A compound of the formula I

wherein R¹ is selected from any one of (i) phenyl;

(ii) pyridinyl

(iii) thienyl

(iv) fuiranyl

(v) imidazolyl

(vi) triazolyl

(vii) pyrrolyl

(viii) thiazolyl

(ix) pyridyl-N-oxide

where each R¹ phenyl ring and R¹ heteroaromatic ring may independentlybe further substituted by 1, 2 or 3 substituents independently selectedfrom straight and branched C₁-C₆ alkyl, NO₂, CF₃, C₁-C₆ alkoxy, chloro,fluoro, bromo, and iodo, as well as salts thereof.
 2. A compoundaccording to claim 1, wherein each R¹ phenyl ring and R¹ heteroaromaticring may independently be further substituted by 1, 2 or 3 substituentsindependently selected from methyl, CF₃, chloro, fluoro, bromo, andiodo.
 3. A compound according to claim 1, wherein each R¹ phenyl ringand R¹ heteroaromatic ring may independently be further substituted by amethyl group.
 4. A compound according to claim 1, wherein R¹ ispyridinyl, pyrrolyl, thienyl or furanyl.
 5. A compound according toclaim 1, selected from any one of[(1-Benzyl-piperidin-4-yl)-(4-diethyl-carbamoyl-phenyl)-amnino]-fluoro-benzamide,[(4-Diethylcarbamoyl-phenyl)-(1-pyridin-2-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide,[(4-Diethylcarbamoyl-phenyl)-(1-thiophen-3-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide,[(4-Diethylcarbamoyl-phenyl)-(1-furan-3-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide,[(4-Diethylcarbamoyl-phenyl)-(1-thiophen-2-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide,[[1-(2,4-Dichloro-benzyl)-piperidin4yl]-(4-diethylcarbam-oyl-phenyl)-amino]-fluoro-benzamide,[(4-Diethylcarbamoyl-phenyl)-(1-thiazol-2-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide,[[1-(4-Bromo-benzyl)-piperidin-4-yl]-(4diethylcarbamoyl-phenyl)-amino]-fluoro-benzamide,[(4-Diethylcarbamoyl-phenyl)-(1-furan-2-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide,[(4-Diethylcarbamoyl-phenyl)-(1-pyridin-4-ylmethyl-piperidin4-yl)-amino]-fluoro-benzamide,[[1-(4Chloro-benzyl)-piperidin-4-yl]-(4-diethylcarbamoyl-phenyl)-amino]-fluoro-benzamide,[(4-Diethylcarbamoyl-phenyl)-(1-pyridin-3-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide,{(4-Diethylcarbamoyl-phenyl)-[1-(3H-imidazol-4-ylmethyl)-piperidin-4-yl]-amino}-fluoro-benzamide{(4-Diethylcarbamoyl-phenyl)-[1-(1H-imidazol-2-ylmethyl)-piperidin]-amino}-fluoro-benzamideand{(4-Diethylcarbamoyl-phenyl)-[1-(1H-pyrrol-2-ylmethyl)-piperidin-4-yl]-amino}-fluoro-benzamide.6. A compound according to any of the preceding claims, in form of itshydrochloride, dihydrochloride, sulfate, tartrate, ditrifluoroacetate orcitrate salts.
 7. A process for preparing a compound of formula I,comprising reacting a compound of the general formula II

wherein PG is a urethane protecting group, such as Boc and CBZ, orbenzyl or substituted benzyl protecting group, such as2,4-dimethoxybenzyl, with N,N-diethyl-4-bromobenzamide, using apalladium catalyst, e.g. Pd₂(dba)₃, in the presence of a base, e.g.sodium tert-butoxide, to give the compounds of general formula III,

which is thereafter deprotected, under standard conditions and alkylatedunder reductive conditions with a compound of the general formula R¹—CHOto give compounds of the general formula I.
 8. A compound according toclaim 1 for use in therapy.
 9. Use of a compound according to formula Iof claim 1 for the manufacture of a medicament for use in the treatmentof pain, anxiety or functional gastrointestinal disorders.
 10. Apharmaceutical composition comprising a compound of the formula Iaccording to claim 1 as an active ingredient, together with apharmaceutically acceptable carrier.
 11. A method for the treatment ofpain, whereby an effective amount of a compound of the formula Iaccording to claim 1 is administered to a subject in need of painmanagement.
 12. A method for the treatment of gastrointestinaldisorders, whereby an effective amount of a compound of the formula Iaccording to claim 1, is administered to a subject suffering from saidgastrointestinal disorder.
 13. A method for the treatment of spinalinjuries, whereby an effective amount of a compound of the formula Iaccording to claim 1, is administered to a subject suffering from saidspinal injury.
 14. A compound of the general formula III

wherein PG is a urethane protecting group, such as Boc and CBZ, orbenzyl or substituted benzyl protecting group, such as2,4-dimethoxybenzyl.
 15. A compound of the general formula X

wherein R¹ is selected from any one of phenyl, pyridinyl, thienyl,furanyl, imidazolyl, triazolyl, pyrrolyl, thiazolyl, or pyridyl-N-oxide.wherein PG is a urethane protecting group, such as Boc and CBZ, orbenzyl or substituted benzyl protecting group, such as2,4-dimethoxybenzyl.